Field of the Invention
The present invention relates to the use of American Ginseng (Panax quinquefolius) to increase neurocognitive function (for example, memory, attention, and calmness, among others).
Description of the Related Art
The term “Ginseng” is generally used to refer to the species of the genus Panax of the family Araliaceae. Extracts of Asian Ginseng (Panax ginseng) have been used for millennia in Traditional Chinese Medicine for the prevention and treatment of a variety of diseases, and have been also used as general health elixirs and performance enhancers (including in the neurocognitive area). There is a growing body of evidence to support Asian Ginseng as a cognitive enhancer. American Ginseng (Panax quinquefolius) is also in the family Araliaceae, although until now the cognition-enhancing properties of American Ginseng have not been known.
Research evaluating behavioural effects of chronic administration of Asian Ginseng in animals has demonstrated attenuation of learning deficits in aged rodents (Wen, T. C. et al. (1996) “Ginseng root prevents learning disability and neuronal loss in gerbils with 5-minute forebrain ischemia,” Acta Neuropathol 91:15-22; Zhao, R. & McDaniel, K. (1998) “Ginseng improves strategic learning by normal and brain-damaged rats,” NeuroReport 9:1619-1624; Nitta, H. et al. (1995) “Panax Ginseng extract improves the scopolamine-induced disruption of 8-arm radial maze performance in rats” Biol Pharm Bull 18:1439-1442). In one study, not only was learning improved in gerbils with learning deficits associated with forebrain ischemia, but Asian Ginseng was also neuroprotective, rescuing hippocampal CA1 pyramidal neurons (Wen et al. 1996). In young rodents, Asian Ginseng-related improvements may follow an inverted U-dose response. Mice administered 3, 10, 30, 100 & 300 mg/kg Asian (extract G115) improved performance following 10 mg/kg in an inverted-U-dose-response manner. However, this effect was observed for a selection of tasks only (Petkov, V. D. & Mosharrof, A. H. (1987) “Effects of standardized Ginseng extract on learning, memory and physical capabilities,” Am J Chin Med 15:19-29). Studies have observed cognitive benefits over a range of dosages of Asian Ginseng, ranging from 10 mg/kg to 150 mg/kg (Petkov & Mosharrof, 1987; Petkov V. D. et al. (1993) “Memory effects of standardized extracts of Panax Ginseng (G115), Ginkgo biloba (GK 501) and their combination Gincosan (PHL-00701),” Planta Med 59:106-114), with some doses appearing to impair cognitive function. For example, Petkov & Mosharrof (1987) found that higher dosages of Asian Ginseng G115 (300 mg/kg) impaired conditioned reflex activity in rats. The dose-response profile of Asian Ginseng is further complicated by variations in methods of assessment, age and dosage (Petkov et al. 1993).
In the few chronic administration studies on human subjects beneficial effects of Asian Ginseng were observed in cognitive deficit populations. For example, Neri et al. administered an Asian Ginseng-containing vitamin complex or placebo for 9 months and examined performance of participants suffering from age-related cognitive decline (Neri, M. et al. (1995) “Influence of a double blind pharmacological trial on two domains of well being in subjects with age associated memory impairment,” Arch Gerontol Geriatr 21:241-252). They observed improvement of mnemonic performance following Asian Ginseng. In non-insulin dependent diabetic patients 8-week administration of 200 mg Asian Ginseng improved psychophysical performance compared to placebo (Sotaniemi, E. A. et al. (1995) “Ginseng therapy in non-insulin-dependent diabetic patients,” Diabetes Care 18:1373-1375). One study aimed to assess the effects of an Asian Ginseng supplement combination ‘Gericomplex’ (Asian Ginseng, vitamins, minerals and trace elements) on mental health and wellbeing of geriatric patients. Two capsules were taken daily for 8 weeks, but they failed to observe any cognitive enhancement by the intervention (Thommessen, B. & Laake, K. (1996) “No identifiable effect of Ginseng (Gericomplex) as an adjuvant in the treatment of geriatric patients,” Aging 8:417-420). In healthy individuals over the age of 40 Sorensen & Sonne administered 400 mg of standardized Asian Ginseng extract for 8 to 9 weeks and observed significantly faster reaction times compared to placebo (Sorensen, H. & Sonne, J. (1996) “A double masked study of the effects of Ginseng on cognitive functions,” Curr Ther Res 57:959-968). In healthy young individuals D'Angelo et al. found that following 12 weeks of treatment of either 100 mg of Asian Ginseng (G115) or placebo (taken twice daily), patients administered Asian Ginseng demonstrated mental arithmetic (D'Angelo, L. et al. (1986) “A double-blind, placebo-controlled clinical study on the effect of a standardized Ginseng extract on psychomotor performance in healthy volunteers,” J Ethnopharmacol 16:15-22). However, these data should be interpreted with caution as the above studies have been criticized on a number of methodological issues such as inadequate sample sizes, non-standardised treatments, and inadequate research designs and statistical analysis (see Bahrke, M. S. & Morgan, W. P. (1994) “Evaluation of the ergogenic properties of Ginseng,” Sports Med 18:229-248; Bahrke, M. S. & Morgan, W. P. (2000) “Evaluation of the ergogenic properties of Ginseng: an update,” Sports Med 298:113-133; Kennedy, D. O. et al. (2003) “Modulation of mood and cognitive performance following administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor binding properties,” Neuropsychopharmacology 28: 1871-1881).
In a series of studies assessing the effects of acute administration of Asian Ginseng on cognition in young healthy individuals, enhancement by Asian Ginseng was observed largely for ‘secondary memory’ (a composite of four secondary memory tasks). (Kennedy et al. 2003; Scholey, A. B. & Kennedy, D. O. (2002) “Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: differential interactions with cognitive demand,” Hum Psychopharmacol Clin 17:35-44). In the first study, doses of 200, 400 and 600 mg Asian Ginseng (G115) were administered (Kennedy, D. O., et al. (2001a) “Differential, dose-dependent changes in cognitive performance and mood following acute administration of Ginseng to healthy young volunteers.” Nutr Neurosci 4:295-310). Enhancement of ‘secondary memory’ was found following 400 mg at four post-dose testing sessions, while the lower and higher dosage diminished performance for ‘speed of attention’ (Id.)
In a further study, assessing combinations of Asian Ginseng and Ginkgo (ratio 100:60) at dosages of 320, 640, 960 mg, a similar pattern was observed (Kennedy, D. O. et al. (2001b) “Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/Panax Ginseng combination to healthy young volunteers,” Nutr Neurosci 4:399-412). With performance of secondary memory being improved by 960 mg, and reduced performance on speed of attention for the other dosages (320 and 640 mg) (Id.). A later study, replicated the finding that a 400 mg dosage improves “secondary memory.” Further study also assessed the effect of 200, 400 and 600 mg Asian Ginseng on mental arithmetic performance, where cognitive demand was manipulated (Kennedy, D. O., et al. (2002a) “Modulation of cognition and mood following administration of single doses of Ginkgo biloba, Ginseng and a Ginkgo/Ginseng combination to healthy young adults,” Physiol Behav 72:953-964). Again this task was improved by a 400 mg dosage but only for the most demanding version of the task (Serial Sevens) (Reay, J. L. et al. (2005) “Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity,” J Psychopharmacol. 19(4):357-65; Reay, J. L. et al. (2006) “Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained ‘mentally demanding’ tasks,” J Psychopharmacol. 20(6):771-81.) It appears to be the case that Asian Ginseng or its constituents are capable of producing tangible cognitive enhancing effects and that for Asian Ginseng 200 or 400 mg appears to be an optimal dose for young healthy adults when administered acutely prior to a cognitive test.
The constituents of Asian Ginseng (Panax ginseng) that are thought to contribute to its bioactivity are the ginsenoside saponins Ginsenosides can be classified into three groups on the basis of their chemical structure; the Panaxadiol group (Rb1, Rb2, Rb3, Rc etc.), Panaxatriol group (Re, Rf, Rg1, Rg2, Rh1), and the oleanolic acid group (e.g. Ro).
American Ginseng (Panax quinquefolius), by contrast, has its own characteristic profile exhibiting a high expression of the Ginsenoside Rb1. The American Ginseng extract used in the present study contains 11.65% Ginsenosides (Rb1 (5.68%), Re (2.05%), Rc (1.86%), Rd (1.47%), Rb2 (0.029%), Rg1 (0.027%)).
Many of these ginsenosides have been isolated and evaluated for pharmacological effects in animal and human models. They have been reported to exert effects on the cholinergic system; isolated Rb1 was both observed to increase synaptosomal choline uptake, and stimulate acetylcholine release (Benishin, C. G. et al. (1991) “Effects of ginsenoside Rb1 on central cholinergic metabolism,” Pharmacology 42:223-229; Benishin, C. G. (1992) “Actions of ginsenoside Rb1 on choline uptake in central cholinergic nerve endings,” Neurochem. Int. 21:1-5). Ginsenosides Rg1 and Rb1 have also been found to elicit marked alterations in brain serotonin concentrations (Zhang, J. T. et al. (1990) “Preliminary study on antiamnestic mechanism of ginsenoside Rg1 and Rb1,” Chin Med J 103:932-938). Furthermore, Salim found that in rat brains Rb1 increased expression of choline acetyltransferase and nerve growth factor messenger RNA (Salim, K. N. et al. (2004) “Ginsenoside Rb1 regulates ChAT, NGF and trkA mRNA expression in rat brain,” Brain Res Mol Brain Res 1997 47:177-182). Other ginsenosides have also been reported to effect specific physiological mechanisms, ginsenoside Rd has been reported to affect corticosterone secretion (Hiai, S. et al. (1983) “Evaluation of corticosterone secretion-inducing activities of ginsenosides and their prosapogenins and sapogenins,” Chem Pharm Bull (Tokyo) 31(1):168-174) and ginsenosides Rd and Re may inhibit synaptosomal uptake of norepinephrine, dopamine, serotonin and GABA (Tsang, D. et al., (1985) “Ginseng saponins influence on neurotransmitter uptake in rat brain synaptosomes,” Planta Med 47:221-224). Furthermore, in vivo modulation of LTP in the hippocampal formation by Ginsenoside Rb1 has been observed in rats (Abe, K. et al. (1994) “Differential effects of ginsenoside Rb1 and malonylginsenoside Rb1 on long-term potentiation in the dentate gyms of rats,” Brain Res. 649 (1-2):7-11.)
With respect to evaluating potential cognitive enhancement by whole extract American Ginseng (Panax quinquefolius), one study observed that scopolamine induced amnesia in Sprague-Dawley rats was attenuated by administration of American Ginseng. American Ginseng attenuated the scopolamine-associated decrement on performance of the Morris water maze task (spatial learning) and increased choline uptake in synaptosomal preparations (Sloley, B. D., et al. (1999) “American Ginseng extract reduces scopolamine induced amnesia in a spatial learning task,” J Psychiatry Neurosci 24:442-452). However, studies assessing the psychogenic benefits of American Ginseng are rare.